Laura Santambrogio
Alessandra Franco- 1Department of Radiation Oncology, Physiology and Biophysics, Englander Institute of Precision Medicine, Weill Cornell Medicine, New York, NY, United States
- 2University of California San Diego School of Medicine, Department of Pediatrics, La Jolla, CA, United States
The MHC-self immunopeptidome of professional antigen presenting cells is a cognate ligand for the TCRs expressed on both conventional and thymic-derived natural regulatory T cells. In regulatory T cells, the TCR signaling associated with MHC-peptide recognition induces antigen specific as well as bystander immunosuppression. On the other hand, TCR activation of conventional T cells is associated with protective immunity. As such the peripheral T cell repertoire is populated by a number of T cells with different phenotypes and different TCRs, which can recognize the same MHC-self-peptide complex, resulting in opposite immunological outcomes. This article summarizes what is known about regulatory and conventional T cell recognition of the MHC-self-immunopeptidome at steady state and in inflammatory conditions associated with increased T and B cell self-reactivity, discussing how changes in the MHC-ligandome including epitope copy number and post-translational modifications can tilt the balance toward the expansion of pro-inflammatory or regulatory T cells.
Introduction
The main role of the thymus is to generate functionally competent T cells, which respond to pathogens but are tolerant to self-antigens (1). During T cell development the T cell receptor (TCR) of maturing T cells interacts with the MHC-self-peptides presented by different thymic antigen presenting cells. The TCR-MHC-peptide interaction occurs within a great range of affinities and the functional outcome of these interactions results in positive and negative T cell selection of both conventional (Tconv) or regulatory (Treg) T cells (2–4). Overall a “weak” TCR signal is conducive to positive selection, and the majority of Tconv cells are generated within this domain of affinities (3, 4). On the other hand, murine models have established that Treg are generated from a niche of T cells rescued from the negatively selected pool (5, 6).
Once they populate the periphery Tconv cells shape the immune responses from immunity to pathogens, to the cytotoxic engagement of tumor cells (7, 8). Regulatory T cells (Treg) are pivotal to immune homeostasis, implementing immune tolerance to self and symbiotic commensal, monitoring immune responses, and maintaining tissue homeostasis (8–10). Natural Treg (nTreg) are generated in the thymus and peripheral Treg (pTreg) are generated in the periphery, following differentiation from conventional naïve CD4+ T cells when exposed to suboptimal antigen concentration and repeated stimulations, or the commensal microbiome (11). nTreg are strategically located in the T and B cell areas of secondary lymphatic organs where they can control both adaptive arms of the immune response (8). To suppress/regulate immune responses Treg rely on cell-surface inhibitors such as CTLA4 and PD-1 as well as the secretion of inhibitory cytokines including IL-10 and TGF-β (8, 12). Additionally, by sequestering IL-2, they control Tconv proliferation and clonal expansion (13).
As for Tconv, the TCR engagement by the cognate MHC-peptide ligand is also pivotal for Tregs differentiation in the thymus, where the affinity of their TCR for MHC-self-peptides rescues them from clonal deletion and set them apart from Tconv (14). Similarly, in the periphery, the tonic signal of Treg-TCR engagement is necessary to maintain their expansion and insure their suppressor function (14).
In the last decade, diverse Treg sub-phenotypes as well as their TCR repertoires have been investigated, giving insight into Treg heterogenicity as well as contributing to the notion that the Treg TCR repertoire is as broad as that of Tconv (9, 15–17).
However, an area that is very much under-investigated is the fine antigen specificity and the MHC-restricted immunopeptidome recognized by Treg and how much this overlap, or is set apart from the MHC-restricted repertoire recognized by Tconv. More importantly, further research is required to examine how the balance between Tconv and Treg recognition of the same MHC-self-peptide complex shape immune responses.
This review summarizes what is known about Treg self-antigen recognition and the related MHC-immunopeptidome and its interplay with the MHC-immunopeptidome recognized by Tconv at steady state and in inflammatory acute and chronic conditions associated with increased T and B cell autoreactivity.
Recognition of the MHC-self-peptidome: Conventional and regulatory T cells
T cell recognition of cognate MHC-peptide ligands is not an on-off binary switch, since the TCR can “sense” differences between optimal and suboptimal ligands and signal accordingly (18). Agonist peptides, even in low nanomolar concentrations, can stimulate proliferation and effector functions (cytokine production, cytotoxic responses) in CD4+ and CD8+ T cells. Partial agonists require a higher concentration to induce the same T cell responses and secretion of effector lymphokines, antagonist peptides specifically inhibit the response(s) that can be induced by an agonist via single amino acid substitutions of major TCR contacts (18). As such, the α/β T-cell receptor present on CD4+ and CD8+ T cells can distinguish subtle structural variations in the MHC-peptide conformation and translate the affinity/avidity of cognate ligand recognition into distinct T cell responses. The ability of the TCR to conduce distinct signals following peptide-MHC engagement plays a pivotal role in directing Tconv and Treg development. Indeed, in the last decade it has become apparent that, in the thymus, the same MHC-peptide complex can induce thymocyte deletion and generate Tconv and nTreg (19).
During thymic selection TCRs with high MHC-peptide affinity can generate Treg, which is selected for highly stringent recognition of an agonist MHC-self-peptide. At the same time, T cells with low/medium affinity for self-peptides undergo positive selection generating Tconv. Similarly, in the periphery, the same MHC-peptide complex can provide the tonic signal necessary to maintain a peripheral T cell repertoire composed of conventional/effectors and thymic-derived nTreg (20). On the other hand, repeated antigen stimulations can induce the switching of naïve T cells and sub-optimally stimulated pro-inflammatory T cells into pTreg (21).
The peripheral T cell repertoire is populated by a number of T cells with different functional phenotypes (Tconv and Treg) and different TCRs that can recognize the same MHC-self-peptide complex with different affinities and generate pro-inflammatory or regulatory immune responses (22, 23).
Treg directly controls around 30% of the autoreactive T cell population from converting into pathogenic effectors (22, 24). At steady state, pTreg by having a TCR with higher affinity for the same MHC-peptide complex, as compared to Tconv, are likely to require lower antigen concentration and by default, a lower MHC-epitope copy number to be activated. As such, pTreg can directly suppress the immune response of Tconv specific for the same MHC-peptide (25). However, Treg and nTreg in particular, can also effectively suppress Tconv specific for a different MHC-peptide complex through secretion of anti-inflammatory cytokines. However, for this non-cognate suppression to occur, nTreg need to be activated by the recognition of their cognate MHC-peptide ligand for TCR signaling and optimal activation and function (26).
In pathological conditions, changes in the dendritic cell MHC-antigen processing and presentation machinery can affect the selection, affinity, composition, and epitope copy number of the MHC-ligandome (27–30). This is associated with up-regulation in the costimulatory molecule and increased adjuvanticity of the tissue microenvironment, which can tilt the Treg/Tconv balance and favor autoreactivity (30, 31).
We and others have observed and demonstrated that in multiple chronic inflammatory and dysmetabolic conditions there is increased T and B cell autoreactivity (29, 30, 32–37). For example, in cardiovascular disorders elevated circulating levels of autoantibodies targeting cardiac or vascular (29) proteins such as troponin I3, cardiac type (TNNI3) (38), oxidized apolipoproteins (39), as well as ubiquitous inflammation-associated proteins such as heat shock proteins (HSPs) (40) have been reported. Similarly, autoreactive T cells and antibodies specific to several cytosolic self-antigens including glutamate decarboxylase 1 (GAD1), islet cell autoantigen 1 (ICA1), INSM transcriptional repressor 1 (INSM1) and solute carrier family 30 member 8 (SLC30A8) have been reported in the serum of patients with metabolic syndrome and type 2 Diabetes (T2D) (41).
Recently, we demonstrated that in Type 2 Diabetes (T2D), the chronic inflammatory environment increased the MHC II presentation of peptides derived from stress-associated proteins by local dendritic cells, including protein disulfate isomerase-3 (PDIA3) (30). Stress-related responses also induced PDIA3 translocation at the plasma membrane, facilitating auto-Ab recognition (30). Ultimately, the increased presence of the MHC II-restricted PDIA3 peptide and increased titers of IgG2b and IgG3 anti-PDIA3 antibodies with cytotoxic activity aggravated liver tissue damage by tilting the balance from tolerance to autoreactivity (30). The pathogenic connotation of anti-PDIA3 immune responses was evident following the passive transfer of cognate CD4+ T cells and antibodies that induced hepatocyte cytotoxicity (30). Similarly, it was demonstrated that an I-Ab-restricted Apolipoprotein B peptide (ApoB) could induce in vivo Treg or Tconv inflammatory responses under opposite environmental conditions (29, 42, 43).
Since both PDIA3 and ApoB peptides are recognized by both Tconv and Treg the stoichiometry of their MHC presentation contributed to tilt the balance towards tolerance or inflammation. Under physiological conditions, around 0.4 femtomoles of PDIA3 peptide and 0.05 femtomoles of ApoB peptide were presented by I-Ab, however in dysmetabolic conditions, due to a high fat, high sucrose diet, a 40% increase in I-Ab presentation of both PDIA3 and ApoB epitopes was observed (29, 30). We reasoned that at steady state Treg requires lower amounts of self-antigens, or MHC-epitope copy number to be activated, due to their higher affinity TCR, as compared to the Tconv TCR specific for the same MHC-peptide complex (9, 14, 25). However, during acute and chronic inflammatory conditions associated with immunogenic cell death, increased antigen availability and MHC-epitope copy number, associated with an environment rich in pro-inflammatory cytokines and damage-associated-molecular pattern (DAMPs) can activate Tconv even if the same MHC-peptide complex is recognized by Treg and overcome their suppression (29–31).
Translational therapeutic applications: Conventional and regulatory T cell balance
Different strategies in early clinical trials have been designed to optimize Treg expansion to suppress autoreactive T cells and autoimmunity even when the disease is in progress (44, 45). Insulin-derived Treg-activating peptides have been mapped both in NOD mice and T1D humans (46, 47); both peptides have been tested in pre-clinical studies. Initial results indicate that the islet cell function was preserved in patients receiving the peptide treatment, as compared to the no-treatment group (47). In another study, Hsp70-derived peptides have been shown to induce Treg cells in clinical studies of Type 1 Diabetes (T1D) (48) and rheumatoid arthritis (RA) (49). Finally, early phase clinical trials with autoantigen specific therapy in Multiple Sclerosis have also shown promising results in inducing Treg-mediated immune suppression (50–52).
When analyzed for anaphylactic reactions it appears that both dosage, timing, and biophysical properties of MHC-peptide binding play a role. For example, the development of the B9-23 insulin peptide for therapeutic purposes indicated that prolonged administration of the peptide induced anaphylaxis in NOD mice (53). Subsequent MHC-peptide binding studies indicated that MHC-peptide affinity/stability favored Tconv activation over Treg (54). On the other hand, self-peptides administered to over 1000 lupus-prone mice did not indicate any adverse reactions. As shown, histone peptides generated Treg that induced TGF-β-mediated suppression without the Th2 skewing associated with the allergic reactions seen in other autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), Multiple Sclerosis (MS) and T1D in NOD mice (47, 55–57).
The balance between Tconv/Treg MHC-self peptide recognition can also be tilted by protein/peptide post-translational modifications. It has long been recognized that in conditions associated with chronic inflammation or in dysmetabolic conditions an increase in oxidative stress, hyperglycemia and hyperlipidemia contribute to non-enzymatic protein oxidation, glycation, and lipoxidation (58–66). The protein post-translational modifications (PTMs) are carried over during endosomal/proteasomal processing and MHC-loading, generating an immunopeptidome where some of the amino acids are modified by the bulky oxidative residues (29, 63). Since these peptides are not presented in the thymus, they may not engage Treg. At the same Tconv could be activated by the PTM-modified peptides (67, 68). This mechanism has been extensively reported for citrullinated peptides in RA (69, 70), oxidized ApoB peptide in atherosclerosis, and cardiovascular diseases (71), nitrosylated peptides in degenerative brain disorders (72), acetylated and citrullinated peptides in lupus (73) and deamidated peptides in melanoma-associated immunogenicity (74).
Albeit the majority of MHC-self peptides are cognate ligands for both Tconv and Treg, during the last decade few studies have pinpointed MHC-restricted epitopes within the human/mouse self-proteome which strongly induce nTreg. Among those, the best characterized have been epitopes processed from histones, albumin(s), and immunoglobulins; likely, due to their high abundance, differently from most tissue specific self-antigens, they are presented in the thymus, at high copy number, during nTreg development.
Histone epitopes are mostly generated from the processing of nucleosomes of apoptotic cells; as known apoptotic cells are physiologically cleared by the immune system without activating an immune response (75). Indeed, cellular apoptosis is a daily occurrence in different organs, particularly in primary lymphoid organs such as the thymus and bone marrow. Peptides derived from apoptotic cells are presented in MHC I and MHC II restriction to educate maturing T and B cells and, histone peptides have been shown to generate CD4+ and CD8+ Treg (56, 76–80).
The yin/yang balance between immunogenic and tolerogenic responses to the self-peptidome can be best visualized in lupus where several immunogenic self-peptides, derived from nucleosomal histones, inducing effector T cells in lupus nephritis have been mapped (78, 81, 82). The same peptides, when administered in low doses (1 µg, sub-cutaneous every 2 weeks) induced a low-dose tolerance which effectively lowered autoantibody levels, blocked nephritis progression, and markedly diminished inflammatory cell infiltration in the kidneys (77). The low dose antigen therapy was shown to induce regulatory T cell subsets with a CD8+ CD25high, and CD4+CD25high phenotype, which both lowered IFN-γ production by autoreactive pro-inflammatory T cells and induced TGF-β secretion in response to the histone epitopes. Importantly, the Treg-induced suppression was maintained in vivo following passive cell transfer where even low dose tolerance with one self peptide epitope could halt the lupus progression (56). Splenic dendritic cells (DC), but not B cells or macrophages were the antigen presenting cells (APC) responsible for the antigen presentation to Treg and for the expansion of epitope-specific and cross-reactive Treg, that suppressed lupus effector T helper (Th)1 and Th17 cells (56). The peptide-induced Treg in PBMC from patients with lupus depended on TGFβ/ALK-5/pSmad 2/3 signaling. Interestingly the DC pulsed with the tolerogenic histone peptide showed a decreased inflammatory phenotype with down-regulation of CD80, CD86, and CD40 co-stimulatory molecules and decreased MHC class II surface expression, as compared to non-peptide pulsed DC (55, 56).
In a murine model of lupus, immune tolerance could be induced by nasal administration of very low amounts of pathogenic self-peptides leading to the expansion of T cells that secrete TGF-β and low amounts of pro-inflammatory cytokines (55, 83). Histone-based therapy also induced CD8+ Treg cells to stably express FOXP3 and increased levels of CTLA-4, CD103, PD-1, PD-L1, and LAP, when compared to CD8+ T cells from the same patients before undergoing kidney transplant (84). These cells were considerably more potent in their suppressive activity as compared to the CD4+CD25high Treg that appeared during clinical “remission” in lupus patients (84–86). Similar responses were observed upon administration of other known lupus autoantigens such as small nuclear ribonucleoproteins and nuclear ribonucleoproteins (87). To summarize, the Treg cells induced by the histone epitopes directly and indirectly suppressed innate immune cells (DC), T cells, and B cells involved in the pathogenic autoimmune response.
Additionally, histone peptides have also been shown to have immunosuppressive activity by activating a subtype of Treg, named follicular regulatory T cells (Tfrs) (CXCR5high PD-1high and FoxP3+), which are located in B cell follicles of secondary lymphoid organs. Tfrs play pivotal roles in regulating B cell responses and inhibiting the development of auto-Ab (88–91). Histones and nuclear proteins have been shown to induce Tfrs expansion and up-regulation of immunosuppressive genes (92). Once activated Tfrs promote inhibition of germinal center B cells, in particular B cells with a BCR specificity towards nuclear proteins, indicative of antigen-specific Treg suppression (93). However, the histone epitopes can induce Treg that suppresses both antigen specific as well as bystander T and B cells, altogether regulating pathogenic immune responses (93).
The second set of well-characterized Treg epitopes that induced both thymic and peripheral Treg (94–98) were IgG peptides, deriving from the processing of the Fc heavy chain constant region (99–101). Ex vivo elegant studies have shown that in children with Kawasaki disease (KD), an acute pediatric vasculitis of the coronary arteries, IgG administered intravenously (IVIG) were mostly internalized by receptor-mediated phagocytosis, Fcγ receptor (R) II and to a lesser extent FcγRIII, by two myeloid tolerogenic DC populations, CD14+ CDC2 and ILT-4+ CD4+ tmDC. Fc processed peptides induced Treg expansion and IL-10 production by both Treg and the presenting DC, indicating the role of both innate and adaptive tolerogenic responses following Fc heavy chain constant region presentation (97–99, 101, 102).
In a different set of studies, IgG peptides, when administered prior to diabetes insurgence in NOD mice, completely abrogated the development of the disease and, when administered after diabetes insurgence suppressed the disease progression (103), even when injected together with insulin immunogenic peptides (103, 104). Finally, IgG+ B cells have been shown to present immunodominant Fc peptides to nTreg via a unique antigen processing of the surface IgG that differs from the exogenous up-take of IgG by tolerogenic DC. Of interest, the most tolerogenic Fc peptides recognized by Treg bind multiple MHC class II alleles, including DR, DP, and DQ, and share the same sequences in healthy donors and RA subjects (101).
Conclusions
Analyses of the MHC-ligandome recognized by Treg and Tconv are an important endeavor, due to the pivotal role of both cells in immune responses. Even though there is not yet extensive literature on the subject, it appears, as expected, that no MHC-peptide is uniquely recognized by either Treg or Tconv. Indeed, for the peptides analyzed in depth so far, it appears that in the thymus the presented MHC-immunopeptidome generates a T cell repertoire that comprises both Treg and Tconv. At steady states, it is likely that Treg exercise control over Tconv responses due to their thymically-selected high affinity TCR, which requires a lower peptide concentration for Treg activation (1). This low-dose tolerance is likely how tolerance to tissue-specific antigens, notoriously present in low amounts, is generated (50, 52, 56). The same mechanism is exploited by “low-dose” peptide therapies used to activate Treg in many autoimmune diseases. However, Treg also recognizes several MHC-epitopes normally presented at high MHC-copy numbers, such as nuclear proteins, immunoglobulins, and albumins. All these antigens have also been shown to effectively activate Treg and strongly down-modulate inflammation and autoimmunity, as seen in several clinical trials. It has been postulated that this “high-dose tolerance” may be important in maintaining a pool of Treg, easily activated by abundant antigens, which down-regulate immune responses through by-standard suppression and secretion of anti-inflammatory cytokines (97, 102).
Further work is necessary to determine the Treg/Tconv antigen specificity and degeneracy, the role of low dose vs high dose tolerance in relationship to Treg/Tconv generation, TCR affinity avidity, and signaling, as well as the contribution of MHC-epitope copy number to the activation of either T cells and finally, the role of tissue microenvironment in keeping or tilting the Treg/Tconv balance.
Author contributions
All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Marrack P, Lo D, Brinster R, Palmiter R, Burkly L, Flavell RH, et al. The effect of thymus environment on T cell development and tolerance. Cell (1988) 53:627–34. doi: 10.1016/0092-8674(88)90578-8
2. Moran AE, Hogquist KA. T-Cell receptor affinity in thymic development. Immunology (2012) 135:261–7. doi: 10.1111/j.1365-2567.2011.03547.x
3. Janeway CA Jr. Thymic selection: Two pathways to life and two to death. Immunity (1994) 1:3–6. doi: 10.1016/1074-7613(94)90003-5
4. Bevan MJ. In thymic selection, peptide diversity gives and takes away. Immunity (1997) 7:175–8. doi: 10.1016/S1074-7613(00)80520-8
5. Owen DL, Mahmud SA, Sjaastad LE, Williams JB, Spanier JA, Simeonov DR, et al. Thymic regulatory T cells arise via two distinct developmental programs. Nat Immunol (2019) 20:195–205. doi: 10.1038/s41590-018-0289-6
6. Klein L, Robey EA, Hsieh CS. Central CD4(+) T cell tolerance: deletion versus regulatory T cell differentiation. Nat Rev Immunol (2019) 19:7–18. doi: 10.1038/s41577-018-0083-6
7. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell (2010) 140:845–58. doi: 10.1016/j.cell.2010.02.021
8. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev (2011) 241:260–8. doi: 10.1111/j.1600-065X.2011.01018.x
9. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol (2012) 30:531–64. doi: 10.1146/annurev.immunol.25.022106.141623
10. Panduro M, Benoist C, Mathis D. Tissue tregs. Annu Rev Immunol (2016) 34:609–33. doi: 10.1146/annurev-immunol-032712-095948
11. Liston A, Rudensky AY. Thymic development and peripheral homeostasis of regulatory T cells. Curr Opin Immunol (2007) 19:176–85. doi: 10.1016/j.coi.2007.02.005
12. Plitas G, Rudensky AY. Regulatory T cells: Differentiation and function. Cancer Immunol Res (2016) 4:721–5. doi: 10.1158/2326-6066.CIR-16-0193
13. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol (2008) 8:523–32. doi: 10.1038/nri2343
14. Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nat Immunol (2014) 15:1070–8. doi: 10.1038/ni.3004
15. Zemmour D, Zilionis R, Kiner E, Klein AM, Mathis D, Benoist C. Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat Immunol (2018) 19:291–301. doi: 10.1038/s41590-018-0051-0
16. Feuerer M, Hill JA, Mathis D, Benoist C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol (2009) 10:689–95. doi: 10.1038/ni.1760
17. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol (2011) 11:119–30. doi: 10.1038/nri2916
18. Kersh GJ, Allen PM. Essential flexibility in the T-cell recognition of antigen. Nature (1996) 380:495–8. doi: 10.1038/380495a0
19. Cozzo Picca C, Simons DM, Oh S, Aitken M, Perng OA, Mergenthaler C, et al. CD4(+)CD25(+)Foxp3(+) regulatory T cell formation requires more specific recognition of a self-peptide than thymocyte deletion. Proc Natl Acad Sci U.S.A. (2011) 108:14890–5. doi: 10.1073/pnas.1103810108
20. Kuczma MP, Szurek EA, Cebula A, Ngo VL, Pietrzak M, Kraj P, et al. Self and microbiota-derived epitopes induce CD4(+) T cell anergy and conversion into CD4(+)Foxp3(+) regulatory cells. Mucosal Immunol (2021) 14:443–54. doi: 10.1038/s41385-020-00349-4
21. Paiva RS, Lino AC, Bergman ML, Caramalho I, Sousa AE, Zelenay S, et al. Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery. Proc Natl Acad Sci U.S.A. (2013) 110:6494–9. doi: 10.1073/pnas.1221955110
22. Cebula A, Kuczma M, Szurek E, Pietrzak M, Savage N, Elhefnawy WR, et al. Dormant pathogenic CD4(+) T cells are prevalent in the peripheral repertoire of healthy mice. Nat Commun (2019) 10:4882. doi: 10.1038/s41467-019-12820-3
23. Saligrama N, Zhao F, Sikora MJ, Serratelli WS, Fernandes RA, Louis DM, et al. Opposing T cell responses in experimental autoimmune encephalomyelitis. Nature (2019) 572:481–7. doi: 10.1038/s41586-019-1467-x
24. Belkaid Y, Oldenhove G. Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity (2008) 29:362–71. doi: 10.1016/j.immuni.2008.08.005
25. Li MO, Rudensky AY. T Cell receptor signalling in the control of regulatory T cell differentiation and function. Nat Rev Immunol (2016) 16:220–33. doi: 10.1038/nri.2016.26
26. Sakaguchi S, Vignali DA, Rudensky AY, Niec RE, Waldmann H. The plasticity and stability of regulatory T cells. Nat Rev Immunol (2013) 13:461–7. doi: 10.1038/nri3464
27. Santambrogio L. Molecular determinants regulating the plasticity of the MHC class II immunopeptidome. Front Immunol (2022) 13:878271. doi: 10.3389/fimmu.2022.878271
28. Clement CC, Becerra A, Yin L, Zolla V, Huang L, Merlin S, et al. The dendritic cell major histocompatibility complex II (MHC II) peptidome derives from a variety of processing pathways and includes peptides with a broad spectrum of HLA-DM sensitivity. J Biol Chem (2016) 291:5576–95. doi: 10.1074/jbc.M115.655738
29. Clement CC, Nanaware PP, Yamazaki T, Negroni MP, Ramesh K, Morozova K, et al. Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery. Immunity (2021) 54:721–736 e10. doi: 10.1016/j.immuni.2021.02.019
30. Clement CC, Osan J, Buque A, Nanaware PP, Chang YC, Perino G, et al. PDIA3 epitope-driven immune autoreactivity contributes to hepatic damage in type 2 diabetes. Sci Immunol (2022) 7:eabl3795. doi: 10.1126/sciimmunol.abl3795
31. Mercadante ER, Lorenz UM. Breaking free of control: How conventional T cells overcome regulatory T cell suppression. Front Immunol (2016) 7:193. doi: 10.3389/fimmu.2016.00193
32. Winer S, Winer DA. The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance. Immunol Cell Biol (2012) 90:755–62. doi: 10.1038/icb.2011.110
33. McLaughlin T, Liu LF, Lamendola C, Shen L, Morton J, Rivas H, et al. T-Cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol (2014) 34:2637–43. doi: 10.1161/ATVBAHA.114.304636
34. Khan S, Tsai S, Winer DA. Adipose tissue b cells come of age: The AABs of fat inflammation. Cell Metab (2019) 30:997–9. doi: 10.1016/j.cmet.2019.11.007
35. Travers RL, Motta AC, Betts JA, Bouloumie A, Thompson D. The impact of adiposity on adipose tissue-resident lymphocyte activation in humans. Int J Obes (Lond) (2015) 39:762–9. doi: 10.1038/ijo.2014.195
36. Winer S, Paltser G, Chan Y, Tsui H, Engleman E, Winer D, et al. Obesity predisposes to Th17 bias. Eur J Immunol (2009) 39:2629–35. doi: 10.1002/eji.200838893
37. Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med (2011) 17:610–7. doi: 10.1038/nm.2353
38. Leuschner F, Li J, Goser S, Reinhardt L, Ottl R, Bride P, et al. Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction. Eur Heart J (2008) 29:1949–55. doi: 10.1093/eurheartj/ehn268
39. Osborn O, Sears DD, Olefsky JM. Fat-induced inflammation unchecked. Cell Metab (2010) 12:553–4. doi: 10.1016/j.cmet.2010.11.017
40. Huby T, Gautier EL. Immune cell-mediated features of non-alcoholic steatohepatitis. Nat Rev Immunol (2021) 429–43. doi: 10.1038/s41577-021-00639-3
41. de Candia P, Prattichizzo F, Garavelli S, De Rosa V, Galgani M, Di Rella F, et al. Type 2 diabetes: How much of an autoimmune disease? Front Endocrinol (Lausanne) (2019) 10:451. doi: 10.3389/fendo.2019.00451
42. Shaw MK, Tse KY, Zhao X, Welch K, Eitzman DT, Thipparthi RR, et al. T-Cells specific for a self-peptide of ApoB-100 exacerbate aortic atheroma in murine atherosclerosis. Front Immunol (2017) 8:95. doi: 10.3389/fimmu.2017.00095
43. Tse K, Gonen A, Sidney J, Ouyang H, Witztum JL, Sette A, et al. Atheroprotective vaccination with MHC-II restricted peptides from ApoB-100. Front Immunol (2013) 4:493. doi: 10.3389/fimmu.2013.00493
44. Clemente-Casares X, Blanco J, Ambalavanan P, Yamanouchi J, Singha S, Fandos C, et al. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature (2016) 530:434–40. doi: 10.1038/nature16962
45. Chen PP, Cepika AM, Agarwal-Hashmi R, Saini G, Uyeda MJ, Louis DM, et al. Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 pathways and persist long-term in patients. Sci Transl Med (2021) 13:eabf5264. doi: 10.1126/scitranslmed.abf5264
46. Bresson D, Fousteri G, Manenkova Y, Croft M, von Herrath M. Antigen-specific prevention of type 1 diabetes in NOD mice is ameliorated by OX40 agonist treatment. J Autoimmun (2011) 37:342–51. doi: 10.1016/j.jaut.2011.10.001
47. Thrower SL, James L, Hall W, Green KM, Arif S, Allen JS, et al. Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man phase I safety study. Clin Exp Immunol (2009) 155:156–65. doi: 10.1111/j.1365-2249.2008.03814.x
48. Barbera Betancourt A, Lyu Q, Broere F, Sijts A, Rutten V, van Eden W. T Cell-mediated chronic inflammatory diseases are candidates for therapeutic tolerance induction with heat shock proteins. Front Immunol (2017) 8:1408. doi: 10.3389/fimmu.2017.01408
49. de Wolf C, van der Zee R, den Braber I, Glant T, Maillere B, Favry E, et al. An arthritis-suppressive and treg cell-inducing CD4+ T cell epitope is functional in the context of HLA-restricted T cell responses. Arthritis Rheumatol (2016) 68:639–47. doi: 10.1002/art.39444
50. Steinman L, Ho PP, Robinson WH, Utz PJ, Villoslada P. Antigen-specific tolerance to self-antigens in protein replacement therapy, gene therapy and autoimmunity. Curr Opin Immunol (2019) 61:46–53. doi: 10.1016/j.coi.2019.07.011
51. Krishnamurthy B, Selck C, Chee J, Jhala G, Kay TW. Analysis of antigen specific T cells in diabetes - lessons from pre-clinical studies and early clinical trials. J Autoimmun (2016) 71:35–43. doi: 10.1016/j.jaut.2016.03.018
52. Zubizarreta I, Florez-Grau G, Vila G, Cabezon R, Espana C, Andorra M, et al. Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial. Proc Natl Acad Sci U.S.A. (2019) 116:8463–70. doi: 10.1073/pnas.1820039116
53. Liu E, Moriyama H, Abiru N, Miao D, Yu L, Taylor RM, et al. Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9-23 and B:13-23. J Clin Invest (2002) 110:1021–7. doi: 10.1172/JCI0215488
54. Sosinowski T, Eisenbarth GS. Type 1 diabetes: primary antigen/peptide/register/trimolecular complex. Immunol Res (2013) 55:270–6. doi: 10.1007/s12026-012-8367-6
55. Wu HY, Ward FJ, Staines NA. Histone peptide-induced nasal tolerance: suppression of murine lupus. J Immunol (2002) 169:1126–34. doi: 10.4049/jimmunol.169.2.1126
56. Kang HK, Liu M, Datta SK. Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells. J Immunol (2007) 178:7849–58. doi: 10.4049/jimmunol.178.12.7849
57. Vandenbark AA, Rich C, Mooney J, Zamora A, Wang C, Huan J, et al. Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35-55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice. J Immunol (2003) 171:127–33. doi: 10.4049/jimmunol.171.1.127
58. Araki E, Nishikawa T. Oxidative stress: A cause and therapeutic target of diabetic complications. J Diabetes Investig (2010) 1:90–6. doi: 10.1111/j.2040-1124.2010.00013.x
59. Bansal S, Siddarth M, Chawla D, Banerjee BD, Madhu SV, Tripathi AK. Advanced glycation end products enhance reactive oxygen and nitrogen species generation in neutrophils in vitro. Mol Cell Biochem (2012) 361:289–96. doi: 10.1007/s11010-011-1114-9
60. Bonnefont-Rousselot D, Raji B, Walrand S, Gardes-Albert M, Jore D, Legrand A, et al. An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. Metabolism (2003) 52:586–9. doi: 10.1053/meta.2003.50093
61. Ward MS, Fortheringham AK, Cooper ME, Forbes JM. Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease. Curr Opin Pharmacol (2013) 13:654–61. doi: 10.1016/j.coph.2013.06.009
62. Scharf B, Clement CC, Yodmuang S, Urbanska AM, Suadicani SO, Aphkhazava D, et al. Age-related carbonylation of fibrocartilage structural proteins drives tissue degenerative modification. Chem Biol (2013) 20:922–34. doi: 10.1016/j.chembiol.2013.06.006
63. Cannizzo ES, Clement CC, Morozova K, Valdor R, Kaushik S, Almeida LN, et al. Age-related oxidative stress compromises endosomal proteostasis. Cell Rep (2012) 2:136–49. doi: 10.1016/j.celrep.2012.06.005
64. Zolla V, Nizamutdinova IT, Scharf B, Clement CC, Maejima D, Akl T, et al. Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance. Aging Cell (2015) 14:582–94. doi: 10.1111/acel.12330
65. Hardin JA, Cobelli N, Santambrogio L. Consequences of metabolic and oxidative modifications of cartilage tissue. Nat Rev Rheumatol (2015) 11:521–9. doi: 10.1038/nrrheum.2015.70
66. Clement CC, Moncrieffe H, Lele A, Janow G, Becerra A, Bauli F, et al. Autoimmune response to transthyretin in juvenile idiopathic arthritis. JCI Insight (2016) 1:1–18. doi: 10.1172/jci.insight.85633
67. Beltrami A, Rossmann M, Fiorillo MT, Paladini F, Sorrentino R, Saenger W, et al. Citrullination-dependent differential presentation of a self-peptide by HLA-B27 subtypes. J Biol Chem (2008) 283:27189–99. doi: 10.1074/jbc.M802818200
68. Trouw LA, Rispens T, Toes REM. Beyond citrullination: Other post-translational protein modifications in rheumatoid arthritis. Nat Rev Rheumatol (2017) 13:331–9. doi: 10.1038/nrrheum.2017.15
69. Iwasaki T, Nakabo S, Terao C, Murakami K, Nakashima R, Hashimoto M, et al. Long-term follow-up of patients with anti-cyclic citrullinated peptide antibody-positive connective tissue disease: A retrospective observational study including information on the HLA-DRB1 allele and citrullination dependency. Arthritis Res Ther (2020) 22:248. doi: 10.1186/s13075-020-02351-4
70. Konig MF, Giles JT, Nigrovic PA, Andrade F. Antibodies to native and citrullinated RA33 (hnRNP A2/B1) challenge citrullination as the inciting principle underlying loss of tolerance in rheumatoid arthritis. Ann Rheum Dis (2016) 75:2022–8. doi: 10.1136/annrheumdis-2015-208529
71. Taleb A, Witztum JL, Tsimikas S. Oxidized phospholipids on apoB-100-containing lipoproteins: a biomarker predicting cardiovascular disease and cardiovascular events. biomark Med (2011) 5:673–94. doi: 10.2217/bmm.11.60
72. Qu J, Nakamura T, Cao G, Holland EA, McKercher SR, Lipton SA. S-nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by beta-amyloid peptide. Proc Natl Acad Sci U.S.A. (2011) 108:14330–5. doi: 10.1073/pnas.1105172108
73. Dieker J, Berden JH, Bakker M, Briand JP, Muller S, Voll R, et al. Autoantibodies against modified histone peptides in SLE patients are associated with disease activity and lupus nephritis. PloS One (2016) 11:e0165373. doi: 10.1371/journal.pone.0165373
74. Dalet A, Robbins PF, Stroobant V, Vigneron N, Li YF, El-Gamil M, et al. An antigenic peptide produced by reverse splicing and double asparagine deamidation. Proc Natl Acad Sci U.S.A. (2011) 108:E323–31. doi: 10.1073/pnas.1101892108
75. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature (1997) 390:350–1. doi: 10.1038/37022
76. Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature (2000) 407:784–8. doi: 10.1038/35037722
77. Kang HK, Michaels MA, Berner BR, Datta SK. Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J Immunol (2005) 174:3247–55. doi: 10.4049/jimmunol.174.6.3247
78. Kaliyaperumal A, Mohan C, Wu W, Datta SK. Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J Exp Med (1996) 183:2459–69. doi: 10.1084/jem.183.6.2459
79. Michaels MA, Kang HK, Kaliyaperumal A, Satyaraj E, Shi Y, Datta SK. A defect in deletion of nucleosome-specific autoimmune T cells in lupus-prone thymus: role of thymic dendritic cells. J Immunol (2005) 175:5857–65. doi: 10.4049/jimmunol.175.9.5857
80. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human b cell precursors. Science (2003) 301:1374–7. doi: 10.1126/science.1086907
81. Stemmer C, Richalet-Secordel P, van Bruggen M, Kramers K, Berden J, Muller S. Dual reactivity of several monoclonal anti-nucleosome autoantibodies for double-stranded DNA and a short segment of histone H3. J Biol Chem (1996) 271:21257–61. doi: 10.1074/jbc.271.35.21257
82. Kramers K, Stemmer C, Monestier M, van Bruggen MC, Rijke-Schilder TP, Hylkema MN, et al. Specificity of monoclonal anti-nucleosome auto-antibodies derived from lupus mice. J Autoimmun (1996) 9:723–9. doi: 10.1006/jaut.1996.0094
83. Stremska ME, Dai C, Venkatadri R, Wang H, Sabapathy V, Kumar G, et al. IL233, an IL-2-IL-33 hybrid cytokine induces prolonged remission of mouse lupus nephritis by targeting treg cells as a single therapeutic agent. J Autoimmun (2019) 102:133–41. doi: 10.1016/j.jaut.2019.05.005
84. Singh RP, La Cava A, Hahn BH. pConsensus peptide induces tolerogenic CD8+ T cells in lupus-prone (NZB x NZW)F1 mice by differentially regulating Foxp3 and PD1 molecules. J Immunol (2008) 180:2069–80. doi: 10.4049/jimmunol.180.4.2069
85. Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA. Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol (2004) 172:5213–21. doi: 10.4049/jimmunol.172.9.5213
86. Zheng SG, Wang JH, Koss MN, Quismorio F Jr., Gray JD, Horwitz DA. CD4+ and CD8+ regulatory T cells generated ex vivo with IL-2 and TGF-beta suppress a stimulatory graft-versus-host disease with a lupus-like syndrome. J Immunol (2004) 172:1531–9. doi: 10.4049/jimmunol.172.3.1531
87. Hoffman RW, Takeda Y, Sharp GC, Lee DR, Hill DL, Kaneoka H, et al. Human T cell clones reactive against U-small nuclear ribonucleoprotein autoantigens from connective tissue disease patients and healthy individuals. J Immunol (1993) 151:6460–9.
88. Kennedy RB, Grigorova I. B and Th cell response to Ag in vivo: Implications for vaccine development and diseases. Immunol Rev (2020) 296:5–8. doi: 10.1111/imr.12899
89. Turner JS, Benet ZL, Grigorova IL. Signals 1, 2 and b cell fate or: Where, when and for how long? Immunol Rev (2020) 296:9–23. doi: 10.1111/imr.12865
90. Long Y, Li W, Feng J, Ma Y, Sun Y, Xu L, et al. Follicular helper and follicular regulatory T cell subset imbalance is associated with higher activated b cells and abnormal autoantibody production in primary anti-phospholipid syndrome patients. Clin Exp Immunol (2021) 206:141–52. doi: 10.1111/cei.13647
91. Liu X, Zhang W, Han Z. Decreased circulating follicular regulatory T cells in patients with dilated cardiomyopathy. Braz J Med Biol Res (2021) 54:e11232. doi: 10.1590/1414-431x2021e11232
92. Xia X, Yang J, Wang S. Follicular regulatory T cells in systemic lupus erythematosus. J Immunol Res (2021) 2021:9943743. doi: 10.1155/2021/9943743
93. Hao H, Nakayamada S, Yamagata K, Ohkubo N, Iwata S, Inoue Y, et al. Conversion of T follicular helper cells to T follicular regulatory cells by interleukin-2 through transcriptional regulation in systemic lupus erythematosus. Arthritis Rheumatol (2021) 73:132–42. doi: 10.1002/art.41457
94. De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, et al. Activation of natural regulatory T cells by IgG fc-derived peptide “Tregitopes”. Blood (2008) 112:3303–11. doi: 10.1182/blood-2008-02-138073
95. Kessel A, Ammuri H, Peri R, Pavlotzky ER, Blank M, Shoenfeld Y, et al. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol (2007) 179:5571–5. doi: 10.4049/jimmunol.179.8.5571
96. Franco A, Albani S. Translating the concept of suppressor/regulatory T cells to clinical applications. Int Rev Immunol (2006) 25:27–47. doi: 10.1080/08830180500544506
97. Burns JC, Touma R, Song Y, Padilla RL, Tremoulet AH, Sidney J, et al. Fine specificities of natural regulatory T cells after IVIG therapy in patients with Kawasaki disease. Autoimmunity (2015) 48:181–8. doi: 10.3109/08916934.2015.1027817
98. Franco A, Touma R, Song Y, Shimizu C, Tremoulet AH, Kanegaye JT, et al. Specificity of regulatory T cells that modulate vascular inflammation. Autoimmunity (2014) 47:95–104. doi: 10.3109/08916934.2013.860524
99. Franco A, Kumar J, Lin G, Behnamfar N, Hsieh LE, Shimizu C, et al. Pediatric tolerogenic DCs expressing CD4 and immunoglobulin-like transcript receptor (ILT)-4 secrete IL-10 in response to fc and adenosine. Eur J Immunol (2018) 48:482–91. doi: 10.1002/eji.201747139
100. Franco A, Damdinsuren B, Ise T, Dement-Brown J, Li H, Nagata S, et al. Human fc receptor-like 5 binds intact IgG via mechanisms distinct from those of fc receptors. J Immunol (2013) 190:5739–46. doi: 10.4049/jimmunol.1202860
101. Hsieh LE, Sidney J, Burns JC, Boyle DL, Firestein GS, Altman Y, et al. IgG epitopes processed and presented by IgG(+) b cells induce suppression by human thymic-derived regulatory T cells. J Immunol (2021) 206:1194–203. doi: 10.4049/jimmunol.2001009
102. Hsieh LE, Song J, Tremoulet AH, Burns JC, Franco A. Intravenous immunoglobulin induces IgG internalization by tolerogenic myeloid dendritic cells that secrete IL-10 and expand fc-specific regulatory T cells. Clin Exp Immunol (2022) 208:361–71. doi: 10.1093/cei/uxac046
103. Cousens LP, Su Y, McClaine E, Li X, Terry F, Smith R, et al. Application of IgG-derived natural treg epitopes (IgG tregitopes) to antigen-specific tolerance induction in a murine model of type 1 diabetes. J Diabetes Res (2013) 2013:621693. doi: 10.1155/2013/621693
Keywords: MHC class I, MHC class II, immune tolerance, regulatory T cells, antigen processing, antigen presentation, peptides
Citation: Santambrogio L and Franco A (2022) The yin/yang balance of the MHC-self-immunopeptidome. Front. Immunol. 13:1035363. doi: 10.3389/fimmu.2022.1035363
Received: 02 September 2022; Accepted: 07 October 2022;
Published: 02 November 2022.
Edited by:
Bénédicte Manoury, Institut National de la Santé et de la Recherche Médicale (INSERM), FranceReviewed by:
Miguel Alvaro-Benito, Freie Universität Berlin, GermanyCopyright © 2022 Santambrogio and Franco. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Laura Santambrogio, las4011@med.cornell.edu